Lymph node management in melanoma has been controversial for over 100 years. Earlier findings of our study group have contributed to current understanding of several cancers and have established current standards for treatment of melanoma with improved prognostic assessment, identification of patients for appropriate interventions, and prevention of treatment-related morbidity. The current proposal will complete the definition of optimal surgical therapy of regional lymph nodes. These aims will be achieved through the second Multicenter Selective Lymphadenectomy Trial (MSLT2). Aim 1) To determine if immediate completion lymph node dissection enhances the outcomes of patients with melanoma sentinel node metastases The primary endpoint of MSLT2 is melanoma-specific survival comparing patients with positive sentinel lymph nodes (SLN) who are treated by immediate completion lymph node dissection (CLND) to those who are followed using clinical and ultrasound examination. Secondary endpoints include disease-free survival, time to recurrence in the regional lymph node basin, quality of life, and safety. Aim 2) To establish and validate optimal methods of SLN evaluation and prognosis determination Although SLN biopsy has improved staging accuracy in melanoma, gold standard methods for SLN evaluation are not established. The rich data available in trial databases have allowed evaluation of several leading candidate parameters for nodal assessment and prognosis. MSLT2 will validate the methods and allow more precise determination of the need for more therapy or follow up. Aim 3) To determine the utility of novel, currently non-standard evaluation measures: 3a) RT-PCR evaluation of SLN: Some patients with SLN that are negative by standard pathologic evaluation recur and die of melanoma. Retrospective studies suggest that RT-PCR evaluation of lymph nodes can discriminate patients who are or are not at substantial risk of recurrence. Validation of these data prospectively in MSLT2 has the potential to revolutionize SLN evaluation. 3b) Ultrasound follow up of at-risk nodal basins: MSLT2 is systematically evaluating the utility of serial ultrasound of lymph node basins in which a positive sentinel node was identified. The significance of these objectives cannot be overstated. MSLT1 has spared many patients unnecessary surgery, morbidity, anxiety and expense. The current trial will establish a similar standard for patients with sentinel node metastases and either confirm the need for immediate CLND or allow the majority of patients to avoid it.